11β-HSD1抑制剂伊快霉素对ob/ob小鼠的抗肥胖作用研究

Anti-obesity effect of 11β-HSD1 inhibitor equisetin on ob/ob mice

伊快霉素(equisetin,EQST)是海洋来源的半萜类化合物,能有效抑制11β-羟甾体脱氢酶1(11β-hydroxysteroid dehydrogenase 1,11β-HSD1)的酶活性。本研究在整体动物水平考察了EQST对肥胖ob/ob小鼠模型的抗肥胖作用和胰岛素抵抗改善作用。所有动物实验均经首都儿科研究所伦理委员会批准。EQST有效降低肥胖ob/ob小鼠的体重和脂肪重增长及血清脂质水平,改善了肥胖小鼠的脂肪细胞肥大和肝脏空泡变性,并有效控制肥胖小鼠葡萄糖负荷及胰岛素负荷后的血糖水平,表现出良好的抗肥胖和缓解胰岛素抵抗药效。EQST通过抑制11β-HSD1蛋白表达来抑制脂肪结合蛋白4(fatty acid-binding protein 4,FABP4)和过氧化物酶体增殖物激活受体γ(peroxisome proliferators-activated receptorγ,PPARγ)蛋白的表达,并促进产热蛋白(uncoupling protein 1,UCP1)的表达。此外,EQST上调大量脂肪组织线粒体呼吸代谢相关蛋白,并可能通过磷酸肌醇-3-激酶(phosphatidylinositol-3-kinase,PI3K)通路改善肥胖小鼠的胰岛素抵抗作用。因此,EQST通过促进脂肪组织产热和改善胰岛素抵抗来发挥抗肥胖作用,或将为改善肥胖与糖尿病等疾病提供可靠的药物资源。

Equisetin(EQST)belongs to polyketide(PKS)-nonribosomal peptide synthetase(NRPS)type compound with an inhibitory effect of 11β-hydroxysteroid dehydrogenase 1(11β-HSD1)enzyme activity.This study investigated anti-obesity effect and insulin resistance improvement effect of EQST on high-fat diet(HFD)-induced ob/ob mice model.EQST treatment effectively reduced the body weight gain,fat weight gain and blood lipid content of model mice.All animal experiments were approved by the Medical Ethics Committee of Capital Institute of Pediatrics.EQST alleviated adipose tissue expansion and hepatic ballooning degeneration of model mice,and also effectively controlled the blood glucose content after glucose load and insulin load,showed a significant improvement in obesity and insulin resistance.EQST inhibited adipogenic proteins fatty acid-binding protein 4(FABP4)and peroxisome proliferators-activated receptorγ(PPARγ),and upregulated thermogenic protein(uncoupling protein 1,UCP1)through suppressing 11β-HSD1 protein expression.In addition,EQST widely upregulates mitochondrial respiratory metabolism related proteins in adipose tissue and may improve insulin resistance through phosphatidylinositol-3-kinase(PI3K)pathway.Therefore,EQST plays an anti-obesity role by promoting adipose tissue thermogenesis and improving insulin resistance,which may provide reliable clues for improving obesity and diabetes.